The THAP-zinc finger protein THAP1 associates with coactivator HCF-1 and O-GlcNAc transferase: a link between DYT6 and DYT3 dystonias.
THAP1 is a sequence-specific DNA binding factor that regulates cell proliferation through modulation of target genes such as the cell cycle-specific gene RRM1. Mutations in the THAP1 DNA binding domain, an atypical zinc finger (THAP-zf), have recently been found to cause DYT6 dystonia, a neurological disease characterized by twisting movements ... and abnormal postures. In this study, we report that THAP1 shares sequence characteristics, in vivo expression patterns and protein partners with THAP3, another THAP-zf protein. Proteomic analyses identified HCF-1, a potent transcriptional coactivator and cell cycle regulator, and O-GlcNAc transferase (OGT), the enzyme that catalyzes the addition of O-GlcNAc, as major cellular partners of THAP3. THAP3 interacts with HCF-1 through a consensus HCF-1-binding motif (HBM), a motif that is also present in THAP1. Accordingly, THAP1 was found to bind HCF-1 in vitro and to associate with HCF-1 and OGT in vivo. THAP1 and THAP3 belong to a large family of HCF-1 binding factors since seven other members of the human THAP-zf protein family were identified, which harbor evolutionary conserved HBMs and bind to HCF-1. Chromatin immunoprecipitation (ChIP) assays and RNA interference experiments showed that endogenous THAP1 mediates the recruitment of HCF-1 to the RRM1 promoter during endothelial cell proliferation and that HCF-1 is essential for transcriptional activation of RRM1. Together, our findings suggest HCF-1 is an important cofactor for THAP1. Interestingly, our results also provide an unexpected link between DYT6 and DYT3 (X-linked dystonia-parkinsonism) dystonias because the gene encoding the THAP1/DYT6 protein partner OGT maps within the DYT3 critical region on Xq13.1.
Mesh Terms:
Acetylglucosamine, Amino Acid Motifs, Apoptosis Regulatory Proteins, Cell Proliferation, Chromosomes, Human, X, DNA-Binding Proteins, Dystonia, Endothelial Cells, Genetic Diseases, X-Linked, Hela Cells, Host Cell Factor C1, Humans, N-Acetylglucosaminyltransferases, Nuclear Proteins, Promoter Regions, Genetic, Protein Binding, Proteomics, Transcription, Genetic, Tumor Suppressor Proteins, Zinc Fingers
Acetylglucosamine, Amino Acid Motifs, Apoptosis Regulatory Proteins, Cell Proliferation, Chromosomes, Human, X, DNA-Binding Proteins, Dystonia, Endothelial Cells, Genetic Diseases, X-Linked, Hela Cells, Host Cell Factor C1, Humans, N-Acetylglucosaminyltransferases, Nuclear Proteins, Promoter Regions, Genetic, Protein Binding, Proteomics, Transcription, Genetic, Tumor Suppressor Proteins, Zinc Fingers
J. Biol. Chem.
Date: Apr. 30, 2010
PubMed ID: 20200153
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